Bisphosphonates are typically marketed in tablets, and the patient is instructed to take each tablet with a full glass of water in the morning, at least one-half hour before eating or drinking. However certain side effects, including esophageal irritation and mucosal erosion are frequently reported if a tablet is not taken with enough water, or if the patient does not remain in an upright position for at least one-half hour after taking the medication. in order to reduce such side effects it is known to prepare bisphosphonates in effervescent form, e.g Katdare et al., U.S. Pat. No. 5,853,759; U.S. patent application Ser. No. 10/092,083, filed Mar. 6, 2002 and U.S. patent application Ser. No. 10/273,081, filed Oct. 17, 2002, now U.S. Pat. No. 7,488,496; and U.S patent application Ser. No. 11/473,044, filed Jun. 23, 2006, all of which are incorporated herein by reference in their entireties.
In NDA 21-575, Merck and Company reported that of four test formulations of effervescent alendronate meant to be bioequivalent to Fosamax tablets, surprisingly, only two of the formulations had drug absorption comparable to the tablets. These data showed that effervescent and soluble formulations of bisphosphonates can be difficult to prepare as a suitable therapeutic delivery form. NDA 21-575 is a partially redacted document, so it is impossible to determine the full range and extent of components that were problematic.
Soluble effervescent formulations of bisphosphonate drugs have many potential advantages. When patients drink an effervescent liquid, it limits the amount of time in which the solid bisphosphonate is in contact with the esophageal tissue, minimizing the risk of irritation as compared to a tablet, which may lodge in the esophagus. Secondly the consistency of absorption of at least some of the bishosphonates, including alendronate, is enhanced. Thirdly, elderly patients who may experience difficulty in swallowing pills can more easily swallow a liquid formulation.
Regulatory requirements relating to effervescent bisphosphonate formulations required the use of ion chromatographic analytical methods to evaluate formulation stability, This analytical method revealed the formation of previously unknown and uncharacterized degradation products formed in conventional effervescent formulations upon storage.
In the course of conducting stability studies of alendronate formulations, unknown chromatographic peaks were identified after storage of tablets manufactured with conventional components such as polyols, sugar alcohols and other soluble materials known to the prior art for manufacture of effervescent tablets. These unknowns could only be visualized by the specialized and rarely utilized analytical technique of ion chromatography (I.C). I.C. is used to characterize bisphosphonate drug products because of a specific request by the United Kingdom Medicines and Health Regulatory Authority (MERA).
it appears that at elevated temperatures, acid components such as citric acid or citrate salts, in the presence of polyols (e.g. sugars such as sorbitol or materials such as polyethylene glycol or “PEG”) give rise to unknown and unidentified materials. The detection system for I.C. uses very low wavelength ultraviolet light (the ‘far ultraviolet’ wavelength region) Most pharmaceutical products are assayed and detected by conventional chromatographic methods with analyte visualization at higher wavelengths (in the near ultraviolet) which do no detect these unknown peaks.
Investigation established that the degradation product did not come from the bisphosphonate, but involved widely used and standard functional excipients in the formulation. It is thought that these unknowns arise from esterification of sugars in the formulation. Sorbitol citrate reactions were described by Shogren, R. L., Doll, K. M. Gonzalez, S. O., Willett, J. L. Swift, G., Preparation and Properties of Sorbitol Citrate Polyesters Bioenvironmental Polymer Society Meeting. (p 93, Jun. 2006), in which sorbitol citrate polyesters We re prepared by melting mixtures of sorbitol and citric acid, mono- or di-sodium citrate at 110-200° C., then removing water of esterification in a vacuum oven, mixer or twin screw extruder. Esterification was confirmed by FTIR bands at 1735 and 1188 cm-1 and decreases in acid value of 20-80%. Reaction rates increased with increasing temperature, and sorbitol concentrations.
Reaction Chemistry
An acid catalyzed esterification and/or polymerization of acids and polyols (such as citrate and sorbitol or citrate and PEG) is believed to lead to the formation of unknown materials during storage. The instability, as judged by appearance of unknown peaks in I.C. chromatograms, is strongly correlated with elevated temperature of the product during storage. A binary combination of citrate and sorbitol generated the unknown peaks in large quantities. The recent publication by Shogren et al. cited above suggests that citric acid or citrate salts can combine with sugars to produce polyesters via a classic chemical reaction, a Fisher (acid catalyzed) esterification. One would expect that the combination of polyols and citrate, either in the solid phase or in solution could lead to the formation of esterification reaction products.
The problem was addressed by trying to eliminate the materials that give rise to the unknowns when combined with citrate (citrate being a necessary component of the effervescent system). Removal of sorbitol or other polyols from the formulation minimizes or eliminates the appearance of the unknown products, but the challenge then was to produce stable granules or tablets without using conventional pharmaceutical excipients.